Peroxisome proliferator activated receptor (PPAR) is a receptor which was cloned in 1990 as a protein mediating actions of increasing peroxisome that is an intracellular small organ associated with lipolysis (Nature, vol. 347, p. 645 (1990)), and a transcription factor that belongs to a nuclear receptor having a ligand such as estrogen, thyroid hormone, fat-soluble vitamin, etc. Three isoforms of PPARα, PPARδ and PPARγ have been identified so far. It is known that PPARα is mainly expressed in the liver, heart, kidney, adrenal, digestive tract and skeletal muscle and PPARγ in immune systemic organs, large intestine, small intestine, adrenal and adipocytes, and PPARδ is ubiquitarily expressed with no specificity for tissues. Any PPAR forms a stable hetero dimer with retinoid X receptor (RXR) and binds to a specific DNA recognizing sequence of the target gene (PPRE) to control it.
PPARα agonist increases lipoprotein lipase (EMBO Journal, vol. 15, p. 5336 (1996)) and suppresses expression of apoC-III (Journal of Clinical Investigation, vol. 95, p. 705 (1995)) to promote catabolism of triglyceride-rich lipoprotein. Furthermore, a fatty acid transport protein and a binding protein specific for each tissue of liver, muscle, fat, small intestine and the like are induced (Journal of Biological Chemistry, vol. 273, p. 16710 (1998)), to promote uptake of free fatty acid. Furthermore, it strongly increases fatty acid β oxidase localized in the mitochondria and peroxisome (Journal of Biological Chemistry, vol. 273, p. 5678 (1998)). Furthermore, PPARα is reported to regulate positively apoA-I gene in human (Journal of Biological Chemistry, vol. 269, p. 31012 (1994)). As the results, PPARα agonist promotes loss of triglyceride from the blood, decreases triglyceride synthesis and ultra-low-density lipoprotein secretion to decrease serum triglyceride, and increases blood high-density lipoprotein, to ameliorate blood lipid composition. For PPARα agonist, a lipid lowering agent known as fibrate type drugs has been already clinically used, and it is clear that PPARα agonist is useful as a prophylactic and/or therapeutic agent for hyperlipidemia and the like. Furthermore, PPARα agonist is known to have physiological actions induce UCP2 (uncoupling protein-2) which is one of uncoupling proteins inhibiting oxidative phosphorylation which is the last step of ATP production system in the liver and small intestine (Biochemical and Biophysical Research Communications, vol. 257, p. 879 (1999), and Biochimica et Biophysica Acta, vol. 1530, p. 15 (2001)), and also known to induce UCP-3 (uncoupling protein-3) in skeletal muscle (FASEB Journal, vol. 15, p. 833 (2001)). From these facts, it is expected to have anti-obesity action by increase of energy consumption or insulin resistance ameliorating action (Diabetes, vol. 50, p. 411 (2001)). Furthermore, it is reported that PPARα is expressed in human aortic smooth muscle cells, that PPARα agonist suppresses IL-6 induction by the stimulation of IL-1β (Nature, vol. 393, p. 790 (1998)), and that PPARα agonist suppresses VCAM-1 expression of endothelial cells by TNF-α or IL-1β (Circulation, vol. 99, p. 3125 (1999)), which suggests that it suppresses formation of atherosclerosis involving inflammatory process. Furthermore, PPARα agonist is found to increase expression of SR-BI (scavenger receptor B class I) and ABCA1 (ATP binding cassette transporter A1) (Circulation, vol. 101, p. 2411 (2000), and Nature Medicine, vol. 7, p. 53 (2001)), which suggests that it increases cholesterol reverse transport system to act against arteriosclerosis. Furthermore, from the fact that potentiation of ABCA1 expression in the small intestine promotes enteral excretion of free cholesterol (Journal of Clinical Investigation, vol. 108, p. 303 (2001)), PPARα agonist is expected to also have serum cholesterol lowering action. On the other hand, PPARα agonist is reported to reduce fibrinogen serum level in mice (Blood, vol. 93, p. 2991 (1999)), which suggests possibility of suppressing cardiovascular event following plaque formation by suppression of thrombus formation.
Endogenous ligand candidates of PPARδ (also referred to as PPARβ or NUCI for human) includes long chain fatty acid and carbaprostacyclin. PPARδ is universally expressed, especially intensively in intestines, kidney and heart. It is reported that PPARδ selective agonist promotes export of cholesterol dependently on apoA-I in macrophage, fibroblast and enteral cells, increases blood high-density lipoprotein and decreases low-density lipoprotein, fast triglyceride and fast insulin in obesity Rhesus monkey (Proceedings of the National Academy of Sciences of the United States of America, vol. 98, p. 5306 (2001)), and shows an action of increasing HDL-C in db/db mouse (FEBS letters, vol. 473, p. 333 (2000)). Therefore, PPARδ agonist is considered to be able to be a blood lipid composition ameliorating agent, and is likely to be an agent of suppressing or treating arteriosclerotic progress, and further an agent of preventing attack of ischemic cardiac disease and the like by reducing syndrome X risk factor. Furthermore, PPARδ agonist is known to induce differentiation and proliferation of glia cells (Molecular and Cellular Biology, vol. 20, p. 5119 (2000) and Glia, vol. 33, p. 191 (2001)). Furthermore, PPARδ agonist is reported to show an action of promoting differentiation of mouse precursor adipocytes (Journal of Biological Chemistry, vol. 274, p. 21920 (1999); Journal of Biological Chemistry, vol. 275, p. 38768 (2000); Journal of Biological Chemistry, vol. 276, p. 3175 (2001)); an action of promoting expression of UCP-2 and UCP-3 of skeletal muscle cells in rat and human (Journal of Biological Chemistry, 2001, 276, p. 10853 and Endocrinology, vol. 142, p. 4189 (2001)); and an action of inhibiting adrenal medulla cell death by hyperosmolar stress (Journal of Biological Chemistry, vol. 277, p. 21341 (2002)). Furthermore, PPARδ is reported to be involved in colon cancer (Cell, vol. 99, p. 335 (1999) and Proceedings of the National Academy of Sciences of the United States of America, vol. 98, p. 2598 (2001)), implantation in pregnancy (Genes and Development, vol. 13, p. 1561 (1999)), bone resorption action in osteoclasts (Journal of Biological Chemistry, vol. 275, p. 8126 (2000)), apoptosis in inflammation (Genes and Development., vol. 15, p. 3263 (2001)), and control of type II acyl-CoA synthase in brain (Journal of Biological Chemistry, vol. 274, p. 35881 (1999)). Also, for PPARδ agonist, use as a prophylactic and/or therapeutic agent for atherosclerosis is disclosed in the pamphlet of WO92/10468, and use as a therapeutic agent for diabetes mellitus or an anti-obesity agent is disclosed in the pamphlet of WO97/28115.
PPARγ is induced to be expressed in the very beginning of adipocyte differentiation, and plays important roles in adipocyte differentiation as master regulator. In recent years, it is suggested that 15-deoxy-Δ12, 14 prostaglandin J2, which is a metabolite of prostaglandin D2, is an endogenous ligand of PPARγ, and it has been clarified that certain insulin sensitizers represented by thiazolidinedione derivatives have a PPARγ ligand activity and the strength of the activity parallels with a hypoglycemic action or adipocyte differentiation promoting action [Cell, vol. 83, p. 803 (1995); Journal of Biological Chemistry, vol. 270, p. 12953, (1995); Journal of Medicinal Chemistry, vol. 39, p. 655 (1996)]. More recently, it has been elucidated that 1) PPARγ is expressed in the cultured cell derived from human liposarcoma and the addition of PPARγ ligand stops its growth [Proceedings of The National Academy of Sciences of The United States of America, vol. 94, p. 237 (1997)], 2) nonsteroidal anti-inflammatory drugs represented by indomethacin and phenoprofen have a PPARγ ligand activity [Journal of Biological Chemistry, vol. 272, p. 3406 (1997)], 3) PPARγ is highly expressed in activated macrophage, and the addition of its ligand leads to the inhibition of the transcription of the gene involved in inflammation [Nature, vol. 391, p. 79 (1998)], 4) PPARγ ligand inhibits production of inflammatory cytokines (TNFα, IL-1β, IL-6) by monocyte [Nature, vol. 391, p. 82 (1998)] and the like.
Agents of binding to PPAR receptor are disclosed, for example, in the pamphlet of WO00/64876, the pamphlet of WO02/144291, the pamphlet of WO01/79197, the pamphlet of WO00/23442, the pamphlet of WO99/46232, JP-A-2001-261612, the pamphlet of WO01/92201, the pamphlet of WO0/75103, the pamphlet of WO01/60807, the specification of US-A-2002/0037911, the specification of U.S. Pat. No. 6,369,055, the specification of US-A-2002/0022656, the pamphlet of WO97/28149, the specification of US-A-2002/0042441, the pamphlet of WO01/00603, the pamphlet of WO02/18355, the pamphlet of WO02/16331, the pamphlet of WO02/16332, the pamphlet of WO01/16120, the pamphlet of WO97/36579 and the like.
Recently, it has been shown that by the action of free fatty acid on G protein-coupled receptor GPR40 which is expressed in pancreas, insulin secretion from pancreatic β cell is promoted (Nature (advance online publication), Feb. 23, 2003, doi:10.1038/nature01478).
On the other hand, compounds having a furan or thiophene structure are known as those described in the following documents and the like.
The pamphlet of WO00/23442 has described a compound as an agent of binding to PPAR ligand receptor represented by the formula:
[wherein R21 groups are each independently a hydrogen atom, C1-8 alkyl, a halogen atom, C1-4 alkoxy, C1-4 alkylthio, nitro, NR24R25 (wherein R24 and R25 are each independently C1-4 alkyl.), cyano, trifluoromethyl, trifluoromethyloxy, carbocycle or heterocycle (the carbocycle and heterocycle may be substituted with a group selected from C1-4 alkyl, C1-4 alkoxy, a halogen atom or trifluoromethyl.), R22 is a hydrogen atom, C1-8 alkyl, a halogen atom, C1-4 alkoxy, C1-4 alkylthio, nitro, NR24R25 (wherein R24 and R25 are each independently C1-4 alkyl.), cyano, trifluoromethyl or trifluoromethyloxy,    R23 is a hydrogen atom or C1-4 alkyl,    X21 is —N— or —CH—,    X22 and Y20 are each independently —O—, —S— or —NR26— (wherein    R26 is a hydrogen atom or C1-4 alkyl.),    Z20 is —O— or —S(O)p′— (wherein p′ is 0, 1 or 2.),    R27 and R28 are each independently a hydrogen atom or C1-4 alkyl, or C3-7 cycloalkylene with the carbon atom to which they are attached,
is carbocycle or heterocycle, is a double a bond or a triple bond, and    q and r are each independently 1 to 3.],    a non-toxic salt and a hydrate thereof.
JP-A-1989-143856 has disclosed a compound as an anti-allergic and anti-inflammatory agent represented by the formula:
[wherein X30 is —C(R34)═ or —N═,    Y30 is —C(R34)═N—, —N═C(R34)—, —C(R34)═C(R34)—, —O—, —S— or —N(R34)—,    Z30 is —(CH2)n′O—, —(CH2)n′-S—, —(CH2)n′-N(R34)—, —C(═O)—N(R34)—, —(CH2)n′S(O)—, —(CH2)n′SO2—, —C(R34)═C(R34)— or —C═C—,    R31 is —(CHR37)nCOOR33,    n′ is each independently 0 to 5,    R32 is each independently hydrogen, lower alkyl, lower alkoxy, lower alkoxycarbonyl, trifluoromethyl, nitro, cyano or halogen,    R33 is
    W is a bond or —O—, —S—, —N(R34)—,    m′ is 1 to 15,    R34 is each independently hydrogen or lower alkyl, and    R37 is hydrogen or methyl] (the definitions in the formula are excerpted for necessary part), and a pharmaceutically acceptable salt thereof.
PCT Japanese Translation Patent Application Publication No. 1993-507920 has described that a compound represented by the formula:
[wherein Ac is
nC is 0 or 1;     is a bond or not;    Rc is C1-C8 alkyl, C3-C7 cycloalkyl, C3-C8 alkenyl, C3-C8 alkynylphenyl, C7-C8 phenylalkyl, C2-C8 alkanoyl, or, C1-C3 alkyl, trifluoromethyl, hydroxy, C1-C3 alkoxy, or one of the above-mentioned groups mono- or di-substituted with fluorine or chlorine;    Xc is S, O, NR2c, —CH═CH—, —CH═N— or —N═CH—;    R2c is hydrogen, C1-C3 alkyl, phenyl or benzyl;    Yc is CH or N;    Zc is hydrogen, C1-C7 alkyl, C3-C7 cycloalkyl, phenyl, or C1-C 3 alkyl, trifluoromethyl, C1-C3 alkoxy, phenyl, phenoxy, benzyl, benzyloxy, phenyl mono- or di-substituted with fluorine or chlorine;    X′c is O, S, SO or SO2;    Y′c is hydroxy, C1-C3 alkoxy and the like; and    Z′c is hydrogen or C1-C3 alkyl] has hypoglycemic action and blood lipid lowering action.
The pamphlet of WO01/93840 has described compounds represented by the formula:
as an integrin receptor ligand.
The pamphlet of WO01/10847 has described a compound represented by the formulae:
as an integrin receptor ligand.
The pamphlet of WO01/23357 has described a compound represented by the formula:
as an integrin receptor ligand.
The pamphlet of WO01/87038 has described a compound represented by the formula:
as a phosphodiesterase inhibitor.
The pamphlet of WO99/6393 has described a compound represented by the formula:
as an anticancer agent or metastasis suppresser.
JP-A-1997-221476 has described a compound represented by the formulae:
as starting materials of the compound having affinity for vasopressin receptor.
Journal of Medicinal Chemistry, vol. 39, p. 3636 (1996) has described a compound represented by the formula:
as a secretory phospholipase A2 inhibitor.
The pamphlet of WO01/53267 has described a compound represented by the formula:
as a starting material of thrombopoietin receptor agonist.
The pamphlet of WO99/19300 has described a compound represented by the formula:
as a prostaglandin agonist.
CHEMCATS [online] has disclosed compounds represented by the formulae:

As a PPAR agonist, the pamphlet of WO02/092590 has described a furan derivative, the pamphlet of WO02/083616 has described a thiophene derivative, and the pamphlet of WO02/096893, the pamphlet of WO02/096894 and the pamphlet of WO02/096895 have described a thiazole derivative.